Exploration Novel of Pyrazole and Isoxazole Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Structure Activity Relationship Study, and Antibiofilm Activity With Molecular Docking Simulation.
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| Název: | Exploration Novel of Pyrazole and Isoxazole Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Structure Activity Relationship Study, and Antibiofilm Activity With Molecular Docking Simulation. |
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| Autoři: | Saadon KE; Department of Chemistry, Faculty of Science (Girls), Al-Azhar University, Nasr City, Cairo, Egypt., Ragab A; Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo, Egypt.; Chemistry Department, Faculty of Science, Galala University, Galala City, Suez, Egypt., Taha NMH; Department of Chemistry, Faculty of Science (Girls), Al-Azhar University, Nasr City, Cairo, Egypt., Mahmoud NA; Department of Chemistry, Faculty of Science (Girls), Al-Azhar University, Nasr City, Cairo, Egypt., Khalil AK; Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt., Elhagali GAM; Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo, Egypt. |
| Zdroj: | Drug development research [Drug Dev Res] 2025 Dec; Vol. 86 (8), pp. e70189. |
| Způsob vydávání: | Journal Article |
| Jazyk: | English |
| Informace o časopise: | Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8204468 Publication Model: Print Cited Medium: Internet ISSN: 1098-2299 (Electronic) Linking ISSN: 02724391 NLM ISO Abbreviation: Drug Dev Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: New York Ny : Wiley-Liss Original Publication: New York : Alan R. Liss, c1981- |
| Výrazy ze slovníku MeSH: | Pyrazoles*/pharmacology , Pyrazoles*/chemistry , Pyrazoles*/chemical synthesis , Biofilms*/drug effects , Isoxazoles*/pharmacology , Isoxazoles*/chemistry , Isoxazoles*/chemical synthesis , Antifungal Agents*/pharmacology , Antifungal Agents*/chemical synthesis , Antifungal Agents*/chemistry , Anti-Bacterial Agents*/pharmacology , Anti-Bacterial Agents*/chemical synthesis , Anti-Bacterial Agents*/chemistry , Anti-Infective Agents*/pharmacology , Anti-Infective Agents*/chemical synthesis , Anti-Infective Agents*/chemistry, Molecular Docking Simulation ; Microbial Sensitivity Tests ; Structure-Activity Relationship ; Drug Design ; Candida albicans/drug effects ; Bacillus subtilis/drug effects |
| Abstrakt: | Developing new antimicrobial drugs is crucial for combating global drug resistance caused by microbial infections. Here, a new series of pyrazole and isoxazole derivatives were synthesized using a multicomponent reaction based on ethylvanillin and active methylene group as well as binucleophile reagents under basic conditions. The designed derivatives were confirmed using FT-IR, 1 H NMR, 13 C NMR, Mass spectrum, and elemental analysis. Subsequently, all the designed derivatives were evaluated against four bacterial and one fungal strain. The synthesized derivatives demonstrated significant to good antimicrobial activity with low MIC values against the tested strains, especially against Bacillus subtilis, Staphylococcus aureus, and Candida albicans. Notably, four compounds 14, 17, 20, and 24 showed promising MIC values ranging from 7.8 to 62.5 µg/mL) against gram-positive strains and for gram-negative strains (MIC = 31.25-125 µg/mL), compared to gentamycin (15.62 and 31.25 µg/mL), respectively. In addition, these derivatives revealed MIC values from 15.62 to 31.25 µg/mL compared to fluconazole (MIC = 15.62 µg/mL) against C. albicans. Additionally, the structure activity relationships (SAR) were discussed. Moreover, the MBC and MFC values were evaluated and the results exhibited bactericidal and fungicidal properties, except for 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 that demonstrated bacteriostatic activity against B. subtilis. Moreover, the biofilm inhibitory activity of the most promising derivatives demonstrated a dose-dependent effect and inhibit biofilm formation from 96.17 ± 0.004% to 66.04 ± 0.004%. Among these compounds, the 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 emerged as the most active, exhibiting a biofilm inhibitory percentage (BIP) of 96.17 ± 0.004% compared to gentamicin's BIP of 96.44 ± 0.004% at 75% MIC. Finally, a docking simulation of the most promising derivatives was conducted within the active site of Las R, suggesting a potential mode of action, where these derivatives displayed different binding interaction with low binding affinity. Moreover, in-silico oral bioavailability and toxicity profile was predicted for the most promising derivatives and exhibited promising physicochemical properties with a safe toxicity profile, opening up the possibility of the discovery of new antibiotics. (© 2025 Wiley Periodicals LLC.) |
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| Grant Information: | The authors received no specific funding for this work. |
| Contributed Indexing: | Keywords: antimicrobial activity; bacterial biofilm activity; ethyl vanillin; in‐silico ADMET studies; pyrazole and isoxazole |
| Substance Nomenclature: | 0 (Pyrazoles) 0 (Isoxazoles) 0 (Antifungal Agents) 0 (Anti-Bacterial Agents) 0 (Anti-Infective Agents) 3QD5KJZ7ZJ (pyrazole) |
| Entry Date(s): | Date Created: 20251117 Date Completed: 20251117 Latest Revision: 20251117 |
| Update Code: | 20251117 |
| DOI: | 10.1002/ddr.70189 |
| PMID: | 41243604 |
| Databáze: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Developing new antimicrobial drugs is crucial for combating global drug resistance caused by microbial infections. Here, a new series of pyrazole and isoxazole derivatives were synthesized using a multicomponent reaction based on ethylvanillin and active methylene group as well as binucleophile reagents under basic conditions. The designed derivatives were confirmed using FT-IR, <sup>1</sup> H NMR, <sup>13</sup> C NMR, Mass spectrum, and elemental analysis. Subsequently, all the designed derivatives were evaluated against four bacterial and one fungal strain. The synthesized derivatives demonstrated significant to good antimicrobial activity with low MIC values against the tested strains, especially against Bacillus subtilis, Staphylococcus aureus, and Candida albicans. Notably, four compounds 14, 17, 20, and 24 showed promising MIC values ranging from 7.8 to 62.5 µg/mL) against gram-positive strains and for gram-negative strains (MIC = 31.25-125 µg/mL), compared to gentamycin (15.62 and 31.25 µg/mL), respectively. In addition, these derivatives revealed MIC values from 15.62 to 31.25 µg/mL compared to fluconazole (MIC = 15.62 µg/mL) against C. albicans. Additionally, the structure activity relationships (SAR) were discussed. Moreover, the MBC and MFC values were evaluated and the results exhibited bactericidal and fungicidal properties, except for 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 that demonstrated bacteriostatic activity against B. subtilis. Moreover, the biofilm inhibitory activity of the most promising derivatives demonstrated a dose-dependent effect and inhibit biofilm formation from 96.17 ± 0.004% to 66.04 ± 0.004%. Among these compounds, the 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 emerged as the most active, exhibiting a biofilm inhibitory percentage (BIP) of 96.17 ± 0.004% compared to gentamicin's BIP of 96.44 ± 0.004% at 75% MIC. Finally, a docking simulation of the most promising derivatives was conducted within the active site of Las R, suggesting a potential mode of action, where these derivatives displayed different binding interaction with low binding affinity. Moreover, in-silico oral bioavailability and toxicity profile was predicted for the most promising derivatives and exhibited promising physicochemical properties with a safe toxicity profile, opening up the possibility of the discovery of new antibiotics.<br /> (© 2025 Wiley Periodicals LLC.) |
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| ISSN: | 1098-2299 |
| DOI: | 10.1002/ddr.70189 |